Succinate dehydrogenase-deficient renal cell carcinoma

• Rare renal carcinoma (about 0.05–0.2%) caused by dysfunction of mitochondrial succinate dehydrogenase (complex II).
• Mostly germline SDHx variants, chiefly SDHB; less often SDHA, SDHC, SDHD.
• Classic: uniform low-grade eosinophilic cells in solid sheets, nests or tubules.
• Pale, bubbly cytoplasm with vacuoles containing wispy, flocculent eosinophilic inclusions.
• Key IHC: complete loss of granular SDHB with retained internal controls; SDHA retained except in SDHA-deficient tumours.
• Low-grade tumours are usually indolent; high grade, coagulative necrosis and sarcomatoid change carry substantial metastatic risk.
• Linked to hereditary paraganglioma–phaeochromocytoma and SDH-deficient GIST.

Diagnostic pearl: a low-grade eosinophilic renal tumour with flocculent inclusions, even in a few cells, should prompt SDHB.

Clinical

• Young and middle-aged adults (mean 37, range 14–76 in the founding series); slight male predominance.
• Incidental or found on surveillance of SDHx carriers; history of paraganglioma, phaeochromocytoma or SDH-deficient GIST in some.
• Bilateral, multifocal or metachronous tumours occur.

Gross

• Well circumscribed, tan to red-brown, mostly solid, sometimes cystic; can resemble oncocytoma; necrosis or invasion in aggressive tumours.

Gill et al., AJSP 2014

• 36 tumours in 27 patients; 26% bilateral; 94% with classic morphology at least focally. Selected cohort.

Diagnostic pearl: a small circumscribed oncocytic tumour in a young patient, especially if bilateral or multifocal, deserves SDHB.

Architecture

• Solid, nested or lobulated growth with delicate septa; tubules and focal cysts; well circumscribed; peripheral entrapped tubules.

Cells and nuclei

• Uniform cuboidal to polygonal cells with pale eosinophilic, bubbly, wispy or flocculent cytoplasm.
• Round smooth nuclei, fine chromatin, inconspicuous nucleoli, minimal pleomorphism, rare mitoses.

Inclusions

• Pale eosinophilic, flocculent, cloud-like material in vacuoles; widespread or focal.

Other

• Stromal hyalinisation, haemorrhage, cystic degeneration, occasional calcification.

Diagnostic pearl: not simply an oncocytic tumour: the pale flocculent material within vacuolated cells is the most distinctive clue.

• Pale, wispy, cloud-like aggregates within round or irregular vacuoles; best at high power; variable from cell to cell.
• Multiple vacuoles give a bubbly look; some vacuoles are empty.
• Ultrastructure: enlarged abnormal and giant mitochondria; not mucin, granules or degeneration.

Distinctions

• EVT: larger, sharply defined vacuoles in dense cells with prominent nucleoli.
• ESC RCC: coarse basophilic stippling.
• ChRCC: perinuclear halos and prominent membranes.
• Low-grade oncocytic FH-deficient RCC: can look almost identical.

Diagnostic pearl: flocculent inclusions are a strong clue, neither fully sensitive nor pathognomonic; SDHB decides.

• Solid / nested: most common; cohesive sheets and round nests of uniform cells.
• Tubular / acinar: may resemble oncocytoma.
• Cystic: solid-cystic tumours with similar lining.
• Papillary: focal, more prominent in unusual high-grade (often SDHA) tumours; evaluate FH and PRCC.
• Cribriform / glandular: uncommon; mimics CDC.
• High-grade / sarcomatoid: pleomorphic areas with focal or absent classic morphology.

Diagnostic pearl: keep SDH deficiency in the differential of unusual high-grade renal tumours, particularly in younger adults.

• SDHB: complete loss of granular cytoplasmic staining with intact controls (tubules, endothelium, fibroblasts, inflammatory cells); weak diffuse non-granular staining is not retention.
• SDHA: retained in SDHB/C/D tumours, usually lost in SDHA tumours.
• PAX8: usually positive.
• Cytokeratins: often negative (68% negative for all keratins tested in the founding series); EMA focal, often apical (96%).
• CK7, CD117: usually negative (beware CD117+ mast cells).
• GATA3 and L1CAM: frequently positive (overlap with LOT).
• FH: retained.

Diagnostic pearl: SDHB matters more than panCK, CK7 or CD117; keratin negativity is a recognised pitfall.

• SDHB−/SDHA+: classic; SDHB, SDHC or SDHD defect (gene not determinable by IHC).
• SDHB−/SDHA−: SDHA-related defect; confirm molecularly; both stains need internal controls.
• SDHB+/SDHA+: conventional SDH-deficient RCC unlikely if staining is convincingly granular.
• Weak SDHB: may be background; compare with controls; repeat or refer equivocal stains.
• SDHA-mutated but SDHA retained: occurs; SDHA IHC is not an absolute rule-out.

Diagnostic pearl: SDHB loss is the principal evidence; SDHA refines but does not replace molecular identification.

2025 multicentre study (40 patients)

• GATA3 positive 37/39 (95%); L1CAM positive 13/18 (72%); both 12/17 (71%).
• GATA3 nuclear, often diffuse; L1CAM membranous.
• Suggests a distal nephron/principal cell-like program, but does not prove shared origin with LOT.

Diagnostic pearl: a GATA3+/CD117− oncocytic tumour is not automatically LOT; test SDHB when flocculent inclusions are present.

Complex II

• SDHA (catalytic), SDHB (iron-sulfur), SDHC and SDHD (membrane anchors); converts succinate to fumarate and feeds the electron transport chain.
• Biallelic inactivation: germline variant + somatic second hit (LOH, deletion); SDHB predominates.
• Succinate accumulates as an oncometabolite, inhibits α-KG-dependent dioxygenases and causes hypermethylation.
• Parallel to FH deficiency (fumarate), but a distinct defect.

Hereditary implications

• Paraganglioma, phaeochromocytoma and SDH-deficient GIST; negative family history does not exclude.
• Genetic counselling and germline SDHx testing for every confirmed case; cascade testing of relatives.
• SDHD shows parent-of-origin effects relevant to counselling.

Diagnostic pearl: an oncometabolite-driven hereditary carcinoma, not a morphologic variant of oncocytoma.

Renal oncocytoma

• Densely granular homogeneous cytoplasm vs pale, bubbly, flocculent cytoplasm.
• CD117 positive and CK7 scattered vs both usually negative; SDHB retained vs lost.

Chromophobe RCC

• Perinuclear halos, raisinoid nuclei, distinct membranes; CD117 and often CK7 positive; SDHB retained; multiple chromosomal losses.
• SDH-deficient RCC: smooth round nuclei and true vacuoles with flocculent material.

Diagnostic pearl: with focal inclusions SDH-deficient RCC can look identical to oncocytoma; keep a low threshold in young or multifocal cases.

Low-grade oncocytic FH-deficient RCC

• Both bland, vacuolated, flocculent, CK7/CD117 negative and potentially hereditary.
• SDH-d: SDHB lost, FH retained, 2SC not aberrant. FH-d: SDHB retained, FH lost, 2SC positive.
• If SDHB is retained but morphology still suggests a metabolic RCC, add FH and 2SC.

EVT

• Large empty vacuoles, prominent nucleoli, thick-walled vessels; CD117+, SDHB retained.

ESC RCC

• Coarse stippling, solid-cystic, hobnail cysts; CK20+, SDHB retained.

LOT

• Small uniform cells, oedematous transitions; diffuse CK7, CD117−; GATA3/L1CAM overlap; SDHB retained.

Diagnostic pearl: retained SDHB does not make a flocculent oncocytic tumour benign; GATA3/L1CAM cannot separate SDH-d from LOT.

• Papillary RCC: papillae with foamy macrophages, CK7/AMACR; SDHA-deficient tumours can be papillary.
• Collecting duct carcinoma: infiltrative glands with desmoplasia; SDHA-deficient RCC can mimic it, so test SDHB in atypical CDC-like tumours with vacuoles.
• Epithelioid AML: HMB45/Melan-A positive; both can be keratin-poor; PAX8 and SDHB loss help.
• Metastatic SDH-deficient tumours in carriers: confirm renal epithelial lineage (PAX8).

Diagnostic pearl: in a keratin-poor high-grade renal tumour, SDHB is more useful than expanding the keratin panel.

• Pleomorphic nuclei, nucleoli, mitoses, expansile or infiltrative growth, necrosis, sarcomatoid or rhabdoid change.
• High-grade areas may coexist with focal classic areas; extensive transformation may be called unclassified RCC; PAX8 and SDHB loss tie components together.

Gill et al. 2014

• Metastasis in 7/10 high-grade tumours and 4/4 with coagulative necrosis, versus 2/17 low-grade (both with unsampled contralateral tumours).
• Late metastases occur: follow-up should be long.

Diagnostic pearl: necrosis, sarcomatoid change and high-grade nuclei matter far more than focal inclusions or cysts.

1. Cytoplasm: bubbly eosinophilic cells with flocculent inclusions and vacuoles.
2. Context: nested/solid/tubular growth; young age, bilateral disease, SDHx tumour history.
3. SDHB with internal controls.
4. SDHA to refine the subunit.
5. Mimics: CK7/CD117 (oncocytoma, ChRCC, EVT, LOT); FH/2SC for FH-deficient RCC.
6. Confirm: SDHA–SDHD sequencing with copy number; counselling and germline testing.

On biopsy

• Inclusions may be absent; cores may look like oncocytoma; high-grade areas may be missed or may be all that is sampled.
• CK7, CD117 and keratins cannot exclude; equivocal SDHB needs repeat or referral.
• Wording: oncocytic renal neoplasm with features suspicious for SDH deficiency; SDHB and/or molecular testing recommended.

Diagnostic pearl: do not finalise a young patient’s oncocytic biopsy as oncocytoma when the cytoplasm is atypical.

• SDHA-deficient RCC (Kandukuri, AJSP 2026, 5 cases): SDHB lost 5/5, SDHA lost 4/5; papillary and nested 5/5, high grade 4/5, desmoplasia; four first called CDC or high-grade RCC NOS; metastasis 2/4.
• GATA3/L1CAM: 95% and 72% positive; exclude SDH deficiency before calling a GATA3+/CK7−/CD117− tumour another oncocytic entity.
• Mucin: a 2026 case with intracytoplasmic and extracellular mucin, SDHB lost, no recurrence at 49 months; mucin does not exclude.
• High-grade underdiagnosis: classic morphology may be focal; test unclassified high-grade eosinophilic RCCs in younger patients.
• Practice gaps: in a 2026 Italian survey only 5/19 pathologists had seen flocculent inclusions; education matters.

• Rare, predominantly hereditary metabolic RCC; mostly SDHB.
• Young adults; bilateral or multifocal tumours occur.
• Uniform low-grade eosinophilic cells in solid, nested or tubular growth.
• Flocculent inclusions in vacuoles (abnormal mitochondria) are the key clue.
• High-grade, papillary, cribriform and CDC-like variants exist.
• Granular SDHB loss with intact controls is the key test; SDHA loss suggests SDHA, but retention does not fully exclude it.
• PAX8+; keratins may be negative; CK7 and CD117 usually negative; GATA3 and L1CAM frequently positive.
• Low-grade oncocytic FH-deficient RCC is a key mimic.
• High grade and necrosis carry major metastatic risk; late metastases occur.
• Every case needs genetic counselling and germline SDHx testing.